Dataset Information

Quantitative proteomics of CSF from the Alzheimer's disease mouse model 5xFAD

ABSTRACT: The 5xFAD mouse model was used to study the influence of amyloid pathology on the cerebrospinal fluid (CSF) proteome. Therefore, CSF of 7-months old 5xFAD and WT control mice was sampled with an improved collection protocol. Using a minute amount of 5 µL CSF, we applied data dependent and data independent acquisition of the same samples on a Q-Exactive HF mass spectrometer. Comparison of DDA and DIA demonstrate a higher data completeness for DIA. The results show a strong effect on microglia activation exemplified by strongly increased abundances of Trem2 and Cst7. Furthermore, neurodegenerative markers such as neurofilaments and tau (Mapt) were strongly increased for 5xFAD mice.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Alzheimer's Disease

SUBMITTER: Stephan Mueller

LAB HEAD: Stefan Lichtenthaler

PROVIDER: PXD053568 | Pride | 2025-04-15

REPOSITORIES: Pride

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Publications

An Improved Method for Sampling and Quantitative Protein Analytics of Cerebrospinal Fluid of Individual Mice.

Lourbopoulos Athanasios A Müller Stephan A SA Jocher Georg G Wick Manfred M Plesnila Nikolaus N Lichtenthaler Stefan F SF

Molecular & cellular proteomics : MCP 20250327 5

The mouse is the species most commonly used in preclinical research, but protein analytics of murine cerebrospinal fluid (CSF) remains challenging because of low sample volumes (often <10 μl) and frequent contaminations with blood. We developed an improved CSF sampling method that allows routine collection of larger volumes (20-30 μl) of pure CSF from individual mice, enabling multiple protein analytical assays from a single sample. Based on cell counts and hemoglobin ELISAs, we provide an easy ...[more]

PMID: 40157722

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Project description:HIGHTLIGHTS-Improved protocol for ISF collection using microdialysis and CSF sampling in mice.-Combined LC‒MS/MS proteomics ISF and CSF analyses for the validation and description of potential new AD biomarkers.-ISF proteomics analysis to track disease progression at the neuronal and glial levels.-Identification of new biomarker candidates for Alzheimer’s disease.ABSTRACTBackground: Mass spectrometry (MS)-based cerebrospinal fluid (CSF) proteomics is an important method for discovering biomarkers of neurodegenerative diseases. CSF serves as a reservoir for interstitial fluid (ISF), and extensive communication between the two fluid compartments helps to remove waste products from the brain.New method: We performed proteomic analyses of both CSF and ISF fluid compartments using intracerebral microdialysis to validate and detect novel biomarkers of Alzheimer's disease (AD) in APPtg and C57Bl/6J control mice.Results: We identified up to 625 proteins in ISF and 4,483 proteins in CSF samples. By comparing the biofluid profiles of APPtg and C57Bl/6J mice, we detected 37 and 108 significantly up- and downregulated candidates, respectively. In ISF, 7 highly regulated proteins, such as Gfap, Aldh1l1, Gstm1, and Txn, have already been implicated in AD progression, whereas in CSF, 9 out of 14 highly regulated proteins, such as Apba2, Syt12, Pgs1 and Vsnl1, have also been validated to be involved in AD pathogenesis. In addition, we also detected new interesting regulated proteins related to the control of synapses and neurotransmission (Kcna2, Cacng3, and Clcn6) whose roles as AD biomarkers should be further investigated.Comparison with existing methods: This newly established combined protocol provides better insight into the mutual communication between ISF and CSF as an analysis of tissue or CSF compartments alone.Conclusions: The use of multiple fluid compartments, ISF and CSF, for the detection of their biological communication enables better detection of new promising AD biomarkers.KEYWORDSAlzheimer’s disease, CSF, ISF, proteomics, biomarkers, microdialysis, mass spectrometry, protein identification, neurodegeneration, brain fluids, expression profilesDATA AVAILABILITYDOI: 10.17605/OSF.IO/VWQ58PUBLICATIONS using this dataset:1)Gorska et al. 2024, Journal of Neuroscience Methodshttps://doi.org/10.1016/j.jneumeth.2024.1102392) to come

Project description:Neurologic manifestations are among the most frequently reported complications of COVID-19. However, given the paucity of tissue samples and highly infectious nature of the etiologic agent of COVID-19, we have limited information to understand the neuropathogenesis of COVID-19. Therefore to better understand the impact of COVID-19 in brain, we employed mass-spectrometry-based proteomics using data-independent acquisition mode (DIA) to investigate cerebrospinal fluid (CSF) proteins collected from two different non-human primates, Rhesus Macaque and African Green Monkeys for the neurologic effects of the infection. These monkeys exhibited minimal to mild pulmonary pathology but moderate to severe CNS pathology. Our results indicate that CSF proteome changes after infection resolution correspond with bronchial virus abundance during early infection and revealed substantial differences between the infected NHPs and their age-matched uninfected controls, suggesting these differences could reflect altered secretion of CNS factors in response to SARS-CoV-2-induced neuropathology. We also observed the infected animals to exhibit much scattered data distributions as compared to the tightly clustered corresponding controls which suggest the heterogeneity of the CSF proteome change and the host response to the viral infection. In addition, dysregulated CSF proteins were preferentially enriched in functional pathways associated with progressive neurodegenerative disorders, hemostasis and innate immune responses that could influence neuroinflammatory responses following COVID-19. Mapping dysregulated proteins to the Human Brain Protein Atlas found that these proteins tended to be enriched in brain regions that exhibit more frequent injury following COVID-19. It therefore appears reasonable to speculate that such CSF protein changes could serve as signatures for neurologic injury, identify important regulatory pathways in this process, and potentially reveal therapeutic targets to prevent or attenuate the development of neurologic injuries following COVID-19.

			Action	DRS
	20241108_154721_5xFAD_direct_DIA.sne	Other
	CSF_466.raw	Raw
	CSF_467.raw	Raw
	CSF_470.raw	Raw
	CSF_473.raw	Raw